Process for the preparation of 5-(2,4-difluorophenyl)-salicylic acid

ABSTRACT

A process for the preparation of 5-(2,4-difluorophenyl)-salicylic acid comprising the reaction of an organometallic derivative with a suitable substituted benzene in the presence of a transition-metal based catalyst is described.

The present invention relates to a process for the preparation of5-(2,4-difluorophenyl)-salicylic acid by cross-coupling reaction.5-(2,4-difluorophenyl)-salicyclic acid (Merck Index, XI ed., No. 3130,page 495), hereinafter indicated to as compound I, is a drug withanti-inflammatory activity known under the international non-proprietaryname (INN) Diflunisal.

In British patent No. 1,175,212 (Merck & Co.), compound I is prepared byGomberg reaction between a diazonium salt of 2,4-difluoroaniline andanisole, subsequent hydrolysis of the ether group and carboxylation.

However, this method provides compound I in a very low yield because ofthe formation of by-products which can be difficultly separated. Thereason for that is known and it is the fact that Gomberg reaction is notregioselective and, in the specific case of the reaction with anisole,gives a mixture of the three positional ortho, meta and para isomers inwhich the desired compound (para-isomer) is not the main one.

Furthermore, it is known that Gomberg reaction requires a large excessof substrate (anisole) which is consequently used as a solvent.

Therefore, to our knowledge it is clear that the method for thepreparation of compound I described in British patent No. 1,175,212 hasno industrial applicability.

In order to overcome these inconveniences, other methods for thepreparation of compound I comprising the Gomberg reaction with benzene,which does not cause regioselectivity problems, have been studied.

In fact, as far as we know, the only industrial method for thepreparation of compound I is described in U.S. Pat. No. 4,225,730 (Merck& Co.) and comprises the preparation of 2,4-difluoro-biphenyl, theFriedel-Crafts acylation with an acyl derivative of a C₂ -C₅ aliphaticcarboxylic acid in order to obtain a 2,4-difluoro-biphenyl4'-substituted by a C₂ -C₅ alkylcarbonyl group, the oxidation of thiscompound in order to obtain a 2,4-difluoro-biphenyl 4'-substituted by aC₂ -C₅ alkylcarbonyloxy group, the hydrolysis in order to obtain4-(2,4-difluorophenyl)-phenol and the carboxylation of this latter inorder to obtain compound I.

It can be easily noted that, by carrying out the Gomberg reaction withbenzene, the resultant 2,4-difluoro-biphenyl must be functionalized inorder to obtain compound I.

The need to functionalize the biphenyl molecule leads to a relevantincrease in the number of synthetic steps.

It is also known from time in the literature that unsymmetricalbiphenyls can be prepared by reaction between an organometallic compoundand a haloaryl compound in the presence of metal catalysts such as, forexample, palladium and nickel (Org. Synth., 66, 67-74). As far as weknow such a method, in spite of its high versatility, has been neverused either for the difluoroarylation of phenols or derivatives thereofor, more particularly, for the preparation of compound I.

We have now found, and it is an object of the present invention, aprocess for the preparation of compound I comprising the reactionbetween an organometallic derivative of formula

    Ar.sub.1 --Q                                               (II)

and a compound of formula

    Ar.sub.2 --Y                                               (III)

wherein

Q is a copper atom or an MX_(n) group wherein M is a metal selectedamong magnesium, zinc, cadmium, mercury, boron and aluminum and, when Mis magnesium, zinc, cadmium or mercury, X is a chlorine, bromine oriodine atom and n is 1; when M is boron, X is a chlorine, bromine oriodine atom, a hydroxy or a C₁ -C₃ alkoxy and n is 2; when

M is aluminum, X is a C₁ -C₄ alkyl and n is 2;

Y is a chlorine, bromine or iodine atom or a trifluoromethanesulfonyloxygroup;

Ar₁ and Ar₂, different from each other, are a difluorophenyl group offormula ##STR1## or a phenol derivative of formula ##STR2## wherein R isa hydrogen atom, a linear or branched C₁ -C₅ alkyl or an optionallysubstituted phenyl or benzyl; R₁ is a hydrogen atom, a carboxyl group orcarboxyl precursor group;

in the presence of a transition-metal(O)based catalyst;

in order to obtain a biphenylderivative of formula ##STR3## wherein Rand R₁ have the above reported meanings; the optional hydrolysis of theether group and the optional carboxylation or transformation of R₁ intoa carboxyl group.

Preferred examples of transition-metal(O)based catalysts are palladiumor nickel, optionally supported, in the presence of ligands such astriphenylphosphine; the transition-metal(O)based catalysts can beoptionally prepared in situ starting from their salts such as, forexample, nickel chloride, cobalt chloride, nickel acetylacetonate,ferric chloride, palladium chloride, lithium tetrachlorocuprate (Li₂CuCl₄), palladium acetate and palladium acetylacetonate. Exclusively forpractical reasons, palladium tetrakis(triphenylphosphine), nickeltetrakis(triphenylphosphine) or palladium on charcoal in the presence oftriphenylphosphine, optionally prepared in situ according, for example,to the method described in Org. Synth., 66, 67-74, are preferred.

Specific examples of carboxyl precursor groups in the meanings of R₁ aremethyl, hydroxymethyl, optionally protected as ether, formyl or acetyl,optionally protected as acetals or ketals, from which the carboxyl groupcan be obtained by oxidation; salts or esters, such as for examplet.butylester, of the carboxyl group from which the free carboxyl groupcan be obtained by hydrolysis or Meyers oxazolines (J. March--AdvancedOrganic Chemistry--3rd Ed.--John Wiley & Sons Inc., page 425).

The reaction between compound II and compound III is generally carriedout in a solvent such as, for example, tetrahydrofuran, diethyl ether,methyl-t.butyl ether, diamyl ether, dibutyl ether, ethylene glycol,dioxane, toluene, benzene, xylene, ethanol or mixtures thereof.

When the compounds of formula II in which M=Boron are used, the reactionis preferably carried out in the presence of a base and in ahydroalcoholic or aqueous medium optionally in a biphasic systemconstituted by a hydroalcoholic or aqueous medium and by an immiscibleorganic solvent.

Examples of bases are sodium carbonate, potassium carbonate, sodiumbicarbonate, potassium bicarbonate, sodium hydroxide, potassiumhydroxide.

The reaction temperature is generally between -30° C. and 80° C.,preferably between 15° C. and 65° C.

The molar amount of catalyst is between 0.05% and 2%.

The optional hydrolysis of the ether group (R different from hydrogen)is carried out according to known methods.

When the reaction is carried out by using a compound of formula IIwherein R₁ is hydrogen, the obtained biphenylderivative of formula IV(R=H) will be carboxylated according to known methods, preferablyaccording to the methods described in U.S. Pat. No. 4,486,599 (ZambonS.p.A.) in order to obtain compound I.

The compounds of formula II wherein M is boron and Ar₁ is adifluorophenyl group, hereinafter referred to as compound II-A ##STR4##are new and they are a further object of the present invention.

The compounds of formula II wherein Q is a copper atom or an MX_(n)wherein M is different from boron are known or they can be preparedaccording to known methods.

For example, the magnesium halides (Grignard compounds) of formula II(M=Mg) can be prepared from the corresponding haloderivatives of formula

    Ar.sub.1 --Z                                               (V)

wherein

Ar₁ has the above reported meanings and Z is a chlorine, bromine oriodine atom; by reaction with magnesium.

The other organometallic compounds of formula II can be preparedaccording to conventional transmetalation reactions from thecorresponding lithium derivatives.

Alternatively, the compounds of formula II-A wherein X is a hydroxy or aC₁ -C₃ alkoxy group can be prepared from the corresponding Grignardcompounds (II, M=Mg) by reaction with a suitable borate and optionalsubsequent hydrolysis.

Exclusively for practical and economic reasons the Grignard compounds offormula II, which can be directly prepared in situ, are preferably used.

The Grignard compounds of formula II wherein Ar₁ is a group of formula##STR5## and R is a linear or branched C₁ -C₄ alkyl or a benzyl areparticularly preferred.

Another preferred embodiment of the process object of the presentinvention comprises the transformation of the Grignard compounds offormula II into the corresponding boronic acid derivative of formula II(M=B, X=OH).

Also the compounds of formula III are known or they can be preparedaccording to known methods.

In a practical embodiment of the process object of the presentinvention, a Grignard compound of formula II, prepared in situ, isdirectly added to a solution of a compound of formula III and of acatalyst at a temperature between 15° C. and 65° C.

When R is different from hydrogen, after hydrolysis of the ether group,for example by treatment with acids, a compound of formula IV whereinR=H is obtained.

From this latter, compound I is prepared by carboxylation when R₁ =H orby oxidation or hydrolysis, as already described, when R₁ is a carboxylprecursor group.

In another practical embodiment of the process object of the invention,a Grignard compound of formula II, prepared in situ, is directlytransformed into the corresponding boronic acid derivative of formula IIby reaction with a trialkylborate, for example trimethylborate, and bysubsequent hydrolsis at a temperature generally between -20 ° C. and 0°C.

The resultant boronic acid derivative is then added to a mixture of acompound of formula III, of a base and of a catalyst in a suitablesolvent at a temperature between 15° C. and 65° C.

After optional hydrolysis of the ether group, for example by treatmentwith acids, a compound of formula IV wherein R=H is obtained. From thislatter, compound I is prepared by carboxylation when R₁ =H or byoxidation or hydrolysis, as already described, when R₁ is a carboxylprecursor group.

The main advantage of the process object of the present inventionconsists in the fact that it allows to obtain compound I by a simplecross-coupling reaction of already functionalized aryl derivatives, withfew steps and in very high yields.

This advantage is due to the fact that the reaction between compound IIand compound III according to the invention is extremely regio-selectivegiving exclusively the desired isomer of formula IV. Furthermore, theuse of already functionalized starting compounds does not require tofurther functionalize the biphenyl molecule with a consequent decreasein the number of synthetic steps.

Another advantage of the process of the invention is that the catalystis used in very small amounts while keeping mild reaction conditions andhigh yields.

A further advantage of the process object of the invention, which isworth noting, is the easy availability at low costs of the startingcompounds.

Finally, it is clear to one skilled in the art how the process of theinvention is particularly suitable for the industrial application.

In order to better illustrate the present invention the followingexamples are now given.

EXAMPLE 1 Preparation of 4-(2,4-difluorophenyl)-anisole from4-methoxyphenyl-magnesiumbromide and palladiumtetrakis(triphenylphosphine) (2%)

An iodine crystal and, then, some drops of a solution of 4-bromoanisole(8.1 g; 43.34 mmoles) in tetrahydrofuran (31 ml) were added to asuspension of magnesium turnings (1.1 g; 45.5 mmoles--Aldrich) intetrahydrofuran (6 ml).

The mixture was heated up to the beginning of the Grignard reaction.Then, the solution of 4-bromoanisole was added dropwise so as to keepthe reaction mixture under reflux.

At the end of the addition, the mixture was kept under reflux forfurther 30 minutes (solution A).

Palladium tetrakis(triphenylphosphine) (1 g; 0.866 mmoles), preparedfrom PdCl₂ (Fluka) and triphenylphosphine (Fluka), was added to asolution of 1-bromo-2,4-difluorobenzene (8.36 g; 43.34 mmoles) intetrahydrofuran (43.5 ml), de-aerated by vacuum/nitrogen, and thesolution was kept under stirring at 20° C. for 15 minutes (solution B).

Solution A was added to solution B and, then, the mixture was heated toreflux. After 1 hour, the reaction mixture was cooled at 20° C. andpoured into 1N hydrochloric acid (170 ml). After addition of ethyl ether(170 ml), the phases were separated and the organic phase was washedwith 1N hydrochloric acid (170 ml), 8% sodium bicarbonate (170 ml) andwater (170 ml).

After dryness and evaporation of the solvent, the resultant crude (11 g)was purified by column chromatography (silica gel, benzene:n.hexane=1:2)obtaining the desired compound (8.1 g; 80% yield).

Similar results were obtained by using a 0.2% amount of catalyst.

EXAMPLE 2 Preparation of 4-(2,4-difluorophenyl)-phenol.

To a 33% solution of hydrobromic acid in acetic acid (1.5 ml)4-(2,4-difluorophenyl)-anisole (0.22 g; 1 mmole), prepared as describedin example 1, was added.

The mixture was kept under stirring under nitrogen at 50° C. for 66hours. Then, the reaction mixture was evaporated to dryness underreduced pressure and the resultant residue was recovered with a mixturewater:ethyl ether=1:1 (5 ml).

The ethereal phase was separated and washed with aqueous sodiumbicarbonate and, then, dried on sodium sulfate.

After removing the solvent under reduced pressure, the resultant crude(0.17 g) was purified by column chromatography (silica gel,n.hexane:ethyl ether=7:3) obtaining the pure compound (0.15 g). ¹ H-NMR(300 MHz, CDCl₃) δ (ppm): 4.9 (s, 1H); 6.85-7.42 (m, 7H).

EXAMPLE 3 Preparation of 5-(2,4-difluorophenyl)-salicylic acid

CO₂ was bubbled into a solution of sodium methoxide, obtained bydissolving sodium (4.46 g; 0.19 moles) in methanol (100 ml), at 20° C.up to complete conversion of methoxide into sodium methylcarbonate.4-(2,4-difluorophenyl)-phenol (20 g; 0.097 moles), prepared as describedin example 2, was added to the resultant suspension.

The solvent was evaporated, recovering methanol (92 ml), up to atemperature of 120°-130° C. (external bath).

The reaction mixture was kept under nitrogen and the temperature of theexternal bath was gradually increased up to 200° C. and kept under theseconditions for 8 hours.

After cooling, the reaction crude was dissolved in boiling water (800ml).

After filtration and neutralization at pH 7 with concentrated HCl (10ml), K₂ CO₃ (10 g) was added to the solution.

The resultant solution was extracted at warm (80° C.) with1,1,2-trichloroethylene (3×100 ml). From the collected organic extracts,after evaporation of the solvent under reduced pressure,4-(2,4-difluorophenyl)-phenol (1.6 g; 0.008 moles) was obtained.

The aqueous phase, kept at 80° C., was added dropwise to a 15% solutionof hydrochloric acid (200 ml) under stirring.

The resultant suspension was extracted at room temperature with ethylether (300 ml) and the organic phase was separated, dried and evaporatedto obtain 5-(2,4-diflurophenyl)-salicylic acid (21.8 g; 0.087 moles; 98%yield).

EXAMPLE 4 Preparation of 4-(2,4-difluorophenyl)-anisole from4-methoxyphenylmagnesium bromide and palladiumtetrakis(triphenylphosphine) (0.5%)

A suspension of magnesium turnings (1.53 g; 63.6 mmoles-Aldrich) intetrahydrofuran (25 ml) was heated to the reflux temperature understirring and under nitrogen, and then iodine (20 mg) was added.

After decolorization of iodine, a solution of 4-bromoanisole (11.2 g; 60mmoles) in tetrahydrofuran (10 ml) was added dropwise in 1 hour to thesuspension under stirring.

At the end of the addition, the suspension was kept under reflux for 30minutes, then cooled at 20° C. and filtered.

A solution of 4-methoxyphenylmagnesiumbromide was obtained (solution A).

Palladium tetrakis(triphenylphosphine) (0.23 g; 0.2 mmoles), preparedfrom PdCl₂ (Fluka) and triphenylphosphine (Fluka), was added, undernitrogen, to a solution of 1-bromo-2,4-difluorobenzene (7.72 g; 40mmoles) in tetrahydrofuran (5 ml).

The resultant solution was heated under reflux and then solution A wasadded in 16 hours.

At the end of the addition, the reaction mixture was kept under refluxfor 3 hours, cooled at 20° C. and, then, poured into water (100 ml)containing 36% hydrochloric acid (5 ml).

The phases were separated and the aqueous phase was extracted withmethylene chloride (20 ml).

The collected organic phases were evaporated under reduced pressure andthe resultant residue (12 g) was purified by column chromatography(silica gel, toluene:n.hexane=6.4) obtaining the desired compound (8.2g; HPLC titre 91%; 85% yield).

EXAMPLE 5 Preparation of 4-(2,4-difluorophenyl)-anisole from4-methoxyphenylboronic acid and palladium tetrakis(triphenylphosphine)(2%)

A hot solution (60° C.) of 4-methoxyphenylboronic acid (5.32 g; 35mmoles) in ethanol (14 g) was added to a mixture of palladiumtetrakis(triphenylphosphine) (0.81 g; 0.7 mmoles), prepared from PdCl₂(Fluka) and triphenylphosphine (Fluka), benzene (56 g),1-bromo-2,4-difluorobenzene (6.18 g; 32 mmoles) and a 2M aqueous sodiumbicarbonate solution (35 g), kept under stirring and under nitrogen at20° C.

The reaction mixture was heated under reflux and under stirring for 5hours.

After cooling to 20° C. in 1 hour, the reaction mixture was poured intoa mixture of methylene chloride (100 g) and water (50 g).

The organic phase was evaporated to dryness under reduced pressureobtaining the desired compound (8.30 g; HPLC titre 75%; 81% yield).

EXAMPLE 6 Preparation of 4-(2,4-difluorophenyl)-anisole from4-methoxyphenylboronic acid and palladium tetrakis(triphenylphosphine)(0.5%)

The procedure described in example 5 was repeated by using a 0.5%concentration of palladium tetrakis(triphenylphosphine) and adding4-methoxyphenylboronic acid and ethanol at cold.

The desired compound was obtained with HPLC titre 90.63% and 98% yield.

EXAMPLE 7 Preparation of 4-(2,4-difluorophenyl)-anisole from4-methoxyphenylmagnesium bromide and nickel acetylacetonate (2%)

A suspension of magnesium turnings (0.62 g; 25.7 mmoles-Aldrich) in drytetrahydrofuran (19 ml) was heated to the reflux temperature undernitrogen and, then, iodine (30 mg) was added.

After decolorization of iodine, 4-bromoanisole (4.00 g; 21.4 mmoles) wasadded, in 40 minutes, to the suspension.

At the end of the addition, the reaction mixture was kept under refluxfor 90 minutes, let coal up to room temperature and filtered undernitrogen on celite (Merck Index, XI ed., No. 4878, page 787).

A solution of 4-methoxyphenylmagnesiumbromide was obtained (solution A).

Solution A was added dropwise in 45 minutes to a mixture of1-bromo-2,4-difluorobenzene (4.13 g; 21.4 mmoles) and nickelacetylacetonate (0.11 g; 0.43 mmoles-Aldrich) in dry tetrahydrofuran (20ml) cooled at -20° C.

The reaction mixture was kept at -20° C. under stirring and undernitrogen for 24 hours and, then, poured into 1N hydrochloric acid (50ml). Methylene chloride (25 ml) was added.

After filtration on celite (Merck Index, XI ed., No. 4878, page 787) andseparation of the phases, the aqueous phase was extracted again withmethylene chloride.

The collected organic phases were washed with water (15 ml) and dried.

After evaporation of the solvent, the resultant crude (5.32 g) waspurified by column chromatography (silica gel, benzene:n.hexane=1:2)obtaining the desired compound (2.38 g; 50.5% yield).

EXAMPLE 8 Preparation of 4-(2,4-difluorophenyl)-anisole from4-methoxyphenylzinc chloride and palladium tetrakis(triphenylphosphine)(2%)

A 1.7M solution of t.butyllithium (Aldrich) in pentane (11.8 ml) wasadded to a solution of 4-bromoanisole (1.87 g; 10 mmoles) in drytetrahydrofuran (10 ml), cooled at -70° C., while keeping thetemperature between -70° C. and -65° C.

A solution of zinc chloride (2.04 g; 15 mmoles-Aldrich) in drytetrahydrofuran (20 ml) was added, at -70° C., to the resultantsolution.

At the end of the addition, the temperature was let arise up to 15° C.spontaneously.

The solution was filtered and added dropwise to a solution of1-bromo-2,4-difluorobenzene (1.93 g; 10 mmoles) and palladiumtetrakis(triphenylphosphine) (0.23 g; 0.2 mmoles), prepared from PdCl₂(Fluka) and triphenylphosphine (Fluka), in tetrahydrofuran (10 ml), at60° C. in 1 hour.

After 20 hours the reaction mixture was poured into 1N hydrochloric acid(15 ml) and methylene chloride (10 ml) was added.

After separation of the phases, the organic phase was washed with water(5 ml), dried and evaporated to dryness under reduced pressure. Theresultant crude was purified by column chromatography (silica gel,n.hexane:benzene=2:1) obtaining the desired compound (1.19 g; 54%yield).

EXAMPLE 9 Preparation of 4-(2,4-difluorophenyl)-anisole from4-methoxyphenylmagnesiumbromide and palladiumtetrakis(triphenylphosphine) (0.15%)

A suspension of magnesium turnings (0.765 g; 31.8 mmoles-Aldrich) in drytetrahydrofuran (18 ml) and iodine (0.02 g) was heated under reflux andunder nitrogen and 4-bromoanisole (5.61 g; 30 mmoles) was added in 1hour.

At the end of the addition, the suspension was kept under reflux for 1hour and then filtered under nitrogen.

A solution of 4-methoxyphenylmagnesiumbromide was obtained (solution A).

A mixture of 1-bromo-2,4-difluorobenzene (3.86 g; 20 mmoles) andpalladium tetrakis)triphenylphosphine) (0.035 g; 0.03 mmoles), preparedfrom PdCl₂ (Fluka) and triphenylphosphine (Fluka), in drytetrahydrofuran (5 ml) was heated under reflux and under nitrogen and,then, solution A was added in 16 hours.

At the end of the addition, the reaction mixture was kept under refluxfor 4 hours and, then, poured into 1N hydrochloric acid (50 ml).

The phases were separated and the aqueous phase was extracted withmethylene chloride (2×10 ml).

The collected organic phases were evaporated under reduced pressure andthe resultant crude (5 g) was purified by column chromatography (silicagel, n:hexane:benzene=2:1) obtaining the desired compound (3.84 g; 87.5%yield).

EXAMPLE 10 Preparation of 4-(2,4-difluorophenyl)-anisole from4-methoxyphenylmagnesiumbromide and palladium acetate/triphenylphosphine(2%)

A suspension of magnesium turnings (0.62 g; 25.8 mmoles--Aldrich) in drytetrahydrofuran (18 ml) and iodine (0.02 g) was heated under reflux andunder nitrogen and kept under stirring for 30 minutes. 4-Bromoanisole(4.00 g; 21.4 mmoles) was added dropwise in 40 minutes and the reactionmixture was kept under reflux and stirring for 1.5 hours and, then,filtered at warm under nitrogen.

A solution of 4-methoxyphenylmagnesiumbromide was obtained (solution A).

A mixture of 1-bromo-2,4-difluorobenzene (4.13 g; 21.4 mmoles),palladium acetate (0.096 g; 0.43 mmoles--Janssen) and triphenylphosphine(0.45 g; 1.72 mmoles--Fluka) in dry tetrahydrofuran (15 ml) was heatedunder reflux and under nitrogen and, then, solution A was added in 2.5hours.

At the end of the addition, the reaction mixture was kept under stirringand under reflux overnight.

After cooling at room temperature, the mixture was poured into 1Nhydrochloric acid (20 ml).

The phases were separated and the aqueous phase was extracted withmethylene chloride (15 ml).

The collected organic phases were evaporated under reduced pressure andthe resultant crude (4.65 g) was purified by column chromatography(silica gel, n.hexane:benzene=2:1) obtaining the desired compound (3.53g; 75% yield).

EXAMPLE 11 Preparation of 4-(2,4-difluorophenyl)-anisole from4-methoxyphenylmagnesiumbromide and palladiumacetylacetonate/triphenylphosphine (2%)

A suspension of magnesium turnings (0.62 g; 25.8 mmoles--Aldrich) in drytetrahydrofuran (18 ml) and iodine (0.02 g) was heated under reflux andunder nitrogen and kept under stirring for 30 minutes. 4-Bromoanisole(4.00 g; 21.4 mmoles) was added dropwise in 40 minutes and the reactionmixture was kept under reflux and stirring for 1.5 hours and, then,filtered at warm under nitrogen.

A solution of 4-methoxyphenylmagnesiumbromide was obtained (solution A).

A mixture of 1-bromo-2,4-difluorobenzene (4.13 g; 21.4 mmoles),palladium acetylacetonate (0.13 g; 0.43 mmoles), prepared from PdCl₂(Fluka) and acetylacetone (Aldrich), and triphenylphosphine (0.45 g;1.72 mmoles--Fluka) in dry tetrahydrofuran (15 ml) was heated underreflux and under nitrogen and, then, solution A was added in 2.5 hours.

At the end of the addition, the reaction mixture was kept under refluxand stirring overnight.

After cooling at room temperature, the mixture was poured into 1Nhydrochloric acid (20 ml).

The phases were separated and the aqueous phase was extracted withmethylene chloride (15 ml).

The collected organic phases were evaporated under reduced pressure andthe resultant crude (4.42 g) was purified by column chromatography(silica gel, n.hexane:benzene=2:1) obtaining the desired compound (2.97g; 63% yield).

EXAMPLE 12 Preparation of 4-(2,4-difluorophenyl)-anisole from4-methoxyphenylmagnesiumbromide and palladium acetate/triphenylphosphine(0.5%)

A suspension of magnesium turnings (1.53 g; 62.9 mmoles--Aldrich) in drytetrahydrofuran (35 ml) and iodine (0.03 g) was heated under reflux andunder nitrogen and kept under stirring for 30 minutes. 4-Bromoanisole(11.22 g; 60 mmoles) was added dropwise in 1 hour and the reactionmixture was kept under reflux and stirring for 1.5 hours and, then,filtered at warm under nitrogen.

A solution of 4-methoxyphenylmagnesiumbromide was obtained (solution A).

A mixture of 1-bromo-2,4-difluorobenzene (11.58 g; 60 mmoles), palladiumacetate (0.067 g; 0.3 mmoles--Janssen) and triphenylphosphine (0.315 g;1.2 mmoles--Fluka) in dry tetrahydrofuran (7.5 ml) was heated underreflux and under nitrogen and, then, solution A was added in 16 hours.

At the end of the addition, the reaction mixture was kept under stirringand under reflux for 3 hours.

After cooling at room temperature, the mixture was poured into 1Nhydrochloric acid (50 ml).

The phases were separated and the aqueous phase was extracted withmethylene chloride (25 ml).

The collected organic phases were evaporated under reduced pressure andthe resultant crude (11.45 g) was purified by column chromatography(silica gel, n.hexane:benzene=2:1) obtaining the desired compound (10.70g; 81% yield).

EXAMPLE 13 Preparation of 4-(2,4-difluorophenyl)-anisole from4-methoxyphenylmagnesiumbromide and palladiumtetrakis(triphenylphosphine) (0.1%)

A suspension of magnesium turnings (268 g; 11.02 moles--Janssen) intetrahydrofuran (2695 g) was heated at 65° C. under stirring and undernitrogen. Then, iodine (2.7 g) and, after 30 minutes, 4-bromoanisole(2000 g; 10.69 moles), in 1 hour, were added to the reaction mixture.

At the end of the addition, the reaction mixture was kept at 75° C. for1 hour and, then, decanted obtaining a solution ofmethoxyphenylmagnesiumbromide (solution A).

1-Bromo-2,4-difluorobenzene (1966 g; 10.18 moles) was heated undernitrogen at 60° C. and then de-aerated by vacuum/nitrogen. Palladiumtetrakis(triphenylphosphine) (11.76 g; 0.011 moles), prepared from PdCl₂(Fluka) and triphenylphosphine (Fluka), was added and the mixture washeated at 80° C. Solution A was, then, added in 4.5 hours.

At the end of the addition, the reaction mixture was kept at 80° C. for30 minutes, cooled at 55° C. and poured into water and ice (2000 g).

After cooling at 30° C., the phases were separated and the solvent ofthe organic phase was evaporated under reduced pressure. The resultantcrude was crystallized from isopropanol obtaining the desired compound(2070 g; HPLC titre 98.30%, 91% yield).

EXAMPLE 14 Preparation of 4-(2,4-difluorophenyl)-anisole from4-methoxyphenylmagnesiumbromide and palladiumtetrakis(triphenylphosphine) (0.1%)

A suspension of magnesium turnings (2.67 g; 110 mmoles--Pometon) intetrahydrofuran (26.95 g) was heated at 65° C. under stirring and undernitrogen. Then, iodine (0.03 g) and, after 30 minutes, 4-bromoanisole(20 g; 107 mmoles), in 1 hour, were added to the reaction mixture.

At the end of the addition, the reaction mixture was kept at 75° C. for1 hour and, then, decanted obtaining a solution of4-methoxyphenylmagnesiumbromide (solution A).

1-Bromo-2,4-difluorobenzene (19.66 g; 102 mmoles) was heated undernitrogen at 60° C. and then de-aerated by vacuum/nitrogen. Palladiumtetrakis(triphenylphosphine) (0.12 g; 0.11 mmoles), prepared from PdCl₂(Fluka) and triphenylphosphine (Fluka), was added and the mixture washeated at 80° C. and kept under stirring for 30 minutes. Solution A was,then, added in 4 hours.

At the end of the addition, the reaction mixture was kept at 80° C. for30 minutes and, then, toluene (30 ml) was added.

After cooling at 55° C., a 1N aqueous solution of hydrochloric acid (20ml) was added in 10 minutes. The mixture was cooled at 40° C. and thephases were separated.

The solvent of the organic phase was evaporated under reduced pressureobtaining the desired compound (25.26 g; HPLC titre 83.58%; 91% yield).

EXAMPLE 15 Preparation of 4-(2,4-difluorophenyl)-anisole from4-methoxyphenylmagnesiumbromide and palladium acetate/triphenylphosphine(0.1%)

A suspension of magnesium turnings (5.34 g; 220 mmoles--Pometon) intetrahydrofuran (54 g) was heated at 65° C. under stirring and undernitrogen. Then, iodine (0.06 g) and, after 30 minutes, 4-bromoanisole(40 g; 214 mmoles), in 1 hour, were added to the reaction mixture.

At the end of the addition, the reaction mixture was kept at 75° C. for1 hour and, then, decanted obtaining a solution of4-methoxyphenylmagnesiumbromide (solution A).

A mixture of 1-bromo-2,4-difluorobenzene (39.32 g; 204 mmoles),palladium acetate (0.04559 g; 0.203 mmoles--Janssen) andtriphenylphosphine (0.2088 g; 0.796 mmoles--Fluka) was de-aerated byvacuum/nitrogen at 25° C. The mixture was heated at 88° C. and solutionA was added in 4 hours.

At the end of the addition, the reaction mixture was kept at 88° C. for30 minutes and, then, toluene (60 ml) was added.

After cooling at 50° C., a 1N aqueous solution of hydrochloric acid (40ml) was added in 10 minutes. The mixture was cooled at 40° C. and thephases were separated.

The solvent of the organic phase was evaporated under reduced pressureobtaining the desired compound (45.3 g; HPLC titre 95%; 97% yield).

EXAMPLE 16 Preparation of 4-(2,4-difluorophenyl)-anisole from4-methoxyphenylmagnesiumbromide and palladium acetate/triphenylphosphine(0.1%)

A suspension of magnesium turnings (13.5 g; 555 mmoles--Janssen) intetrahydrofuran (132.9 g) was heated at 65° C. under stirring and undernitrogen. Then, iodine (0.35 g) and, after 30 minutes, 4-bromoanisole(102.65 g; 549 mmoles), in 1 hour, were added to the reaction mixture.

At the end of the addition, the reaction mixture was kept at 75° C. for1 hour and, then, decanted obtaining a solution of4-methoxyphenylmagnesiumbromide (solution A).

A mixture of 1-bromo-2,4-difluorobenzene (100 g; 518 mmoles), palladiumacetate (0.11644 g; 0.519 mmoles--Janssen) and triphenylphosphine(0.54356 g; 2.07 mmoles--Fluka) was de-aerated by vacuum/nitrogen at 25°C. The mixture was heated at 85° C., kept under stirring for 15 minutesand, then, solution A was added in 6 hours.

At the end of the addition, the reaction mixture was kept at 85° C. for30 minutes.

After cooling at 60° C., a solution of 37% hydrochloric acid (17.5 ml)in water (88 ml) was added in 20 minutes.

The mixture was cooled at 40° C. and the phases were separated.

The solvent of the organic phase was evaporated under reduced pressureobtaining the desired compound (113 g; HPLC titre 93.71%; 93% yield).

EXAMPLE 17 Preparation of 4-(2,4-difluorophenyl)-anisole from4-methoxyphenylmagnesiumbromide and palladium acetate/triphenylphosphine(0.05%)

A suspension of magnesium turnings (1.54 g; 63.3 mmoles--Pometon) intetrahydrofuran (16.02 g) was heated at 65° C. under stirring and undernitrogen. Then, iodine (0.02 g) and, after 30 minutes, 4-bromoanisole(11.69 g; 62.5 mmoles), in 1 hour, were added to the reaction mixture.

At the end of the addition, the reaction mixture was kept at 75° C. for1 hour and, then, decanted obtaining a solution of4-methoxyphenylmagnesiumbromide (solution A).

A mixture of 1-bromo-2,4-difluorobenzene (11.4 g; 59.1 mmoles),palladium acetate (0.00663 g; 0.0295 mmoles--Janssen) andtriphenylphosphine (0.03074 g; 0.1172 mmoles--Fluka) was de-aerated byvacuum/nitrogen at 25° C. The mixture was heated at 85° C., kept understirring for 15 minutes and, then, solution A was added in 3 hours.

At the end of the addition, the reaction mixture was kept at 85° C. for30 minutes.

After cooling at 60° C., a solution of 37% hydrochloric acid (2 ml) inwater (10 ml) was added in 20 minutes.

The mixture was cooled at 40° C. and the phases were separated.

The solvent of the organic phase was evaporated under reduced pressureobtaining the desired compound (92% yield).

EXAMPLE 18 Preparation of 4-(2,4-difluorophenyl)-anisole from4-methoxyphenylmagnesiumbromide and palladiumchloride/triphenylphosphine (0.1%)

A suspension of magnesium turnings (2.67 g; 110 mmoles--Pometon) intetrahydrofuran (26.95 g) was heated at 65° C. under stirring and undernitrogen. Then, iodine (0.03 g) and, after 30 minutes, 4-bromoanisole(20 g; 107 mmoles), in 1 hour, were added to the reaction mixture.

At the end of the addition, the reaction mixture was kept at 75° C. for1 hour and, then, decanted obtaining a solution of4-methoxyphenylmagnesiumbromide (solution A).

A mixture of 1-bromo-2,4-difluorobenzene (19.66 g; 102 mmoles),palladium chloride (0.01784 g; 0.10 mmoles--Degussa) andtriphenylphosphine (0.10492 g; 0.40 mmoles--Fluka) was de-aerated byvacuum/nitrogen. The mixture was heated at 88° C. and solution A wasadded in 4 hours.

At the end of the addition, the reaction mixture was kept at 88° C. for30 minutes and, then, toluene (30 ml) was added.

After cooling at 55° C., a 1N aqueous solution of hydrochloric acid (20ml) was added in 10 minutes.

The mixture was cooled at 40° C. and the phases were separated.

The solvent of the organic phase was evaporated under reduced pressureobtaining the desired compound (25.26 g; HPLC titre 94.5%; 95% yield).

EXAMPLE 19 Preparation of 4-(2,4-difluorophenyl)-anisole from4-methoxyphenylmagnesiumbromide and palladiumchloride/triphenylphosphine (0.05%)

A suspension of magnesium turnings (1.54 g; 63.3 mmoles-Pometon) intetrahydrofuran (16.02 g) was heated at 65° C. under stirring and undernitrogen. Then, iodine (0.02 g) and, after 30 minutes, 4-bromoanisole(11.69 g; 62.5 mmoles), in 1 hour, were added to the reaction mixture.

At the end of the addition, the reaction mixture was kept at 75° C. for1 hour and, then, decanted obtaining a solution of4-methoxyphenylmagnesiumbromide (solution A).

A mixture of 1-bromo-2,4-difluorobenzene (11.4 g; 59.1 mmoles),palladium chloride (0.00526 g; 0.0297 mmoles--Fluka) andtriphenylphosphine (0.03088 g; 0.1177 mmoles--Fluka) was de-aerated byvacuum/nitrogen at 25° C. The mixture was heated at 85° C., kept understirring for 15 minutes and, then, solution A was added in 3 hours. Atthe end of the addition, the reaction mixture was kept at 85° C. for 30minutes.

After cooling at 60° C., a solution of 37% hydrochloric acid (2 ml) inwater (10 ml) was added in 20 minutes.

The mixture was cooled at 40° C. and the phases were separated.

The solvent of the organic phase was evaporated under reduced pressureobtaining the desired compound (98.5% yield).

EXAMPLE 20 Preparation of 2,4-difluorophenylboronic acid

A) A 1M solution of 2,4-difluorophenylmagnesiumbromide intetrahydrofuran (50 ml) was added dropwise to a solution oftrimethylborate (5.71 g; 55 mmoles--Fluka) in tetrahydrofuran (42 g),cooled at -15° C. and under nitrogen.

At the end of the addition, the reaction mixture was heated at 20° C. in30 minutes, poured into 2N hydrochloric acid (100 g) and, then,extracted with methylene chloride (2×50 g).

The collected organic phases were evaporated to dryness under reducedpressure. The resultant crude (6.78 g) was crystallized from water (60ml) obtaining pure 2,4-difluorophenylboronic acid (5.91 g; 74.8% yield).

m.p. 240°-241° C.

¹ H-NMR (300 MHz, CDCl₃): δ (ppm): 6.8 (m, 1H); 6.94 (m, 1H); 7.83 (m,1H).

¹⁹ F-NMR (283.2 MHz, CDCl₃): δ (ppm, CF₃ COOH): -107.25 (m, 1F); -105.7(m, 1F).

B) Trimethylborate (25.98 g; 0.25 moles--Fluka) and a solution of2,4-difluorophenylmagnesiumbromide (0.25 moles) in tetrahydrofuran (200ml) were contemporaneously added, in 1 hour, into a reactor containingtetrahydrofuran (125 ml) under nitrogen while keeping the temperature at-15° C.

At the end of the addition, the reaction mixture was kept under stirringat -15° C. for 15 minutes.

After bringing the temperature to 0° C., water (17.5 ml) and 10%sulfuric acid (125 ml) were added in 10 minutes and in 15 minutesrespectively.

After adding further water (250 ml) up to complete dissolution, thesolution was extracted with ethyl ether (3×150 ml). The collectedorganic phases were evaporated to dryness obtaining a crude2,4-difluorophenylboronic acid (36.98 g; titre 90%; 84.3% yield) whichwas used in the subsequent cross-coupling reaction without any furtherpurification.

EXAMPLE 21 Preparation of 4-(2,4-difluorophenyl)-anisole from2,4-difluorophenylboronic acid and palladiumtetrakis(triphenylphosphine) (2%)

2,4-Difluorophenylboronic acid (1.00 g; 6.33 mmoles), prepared asdescribed in example 20, and ethanol (2.5 g) were added to a mixture ofpalladium tetrakis(triphenylphosphine) (0.15 g; 0.13 mmoles), preparedfrom PdCl₂ (Fluka) and triphenylphosphine (Fluka), toluene (10 g),4-bromoanisole (1.18 g; 6.30 mmoles) and a 2M aqueous sodium carbonatesolution (6.3 g) kept under stirring at 20° C. and under nitrogen.

The reaction mixture was heated under reflux and stirring for 9 hours.

The reaction mixture, then, cooled at 20° C. in 1 hour and poured into amixture of toluene (12 g) and water (9 g).

The organic phase was evaporated to dryness under reduced pressureobtaining the desired compound (1.58 g; titre 84.16%; 95% yield).

EXAMPLE 22 Preparation of 4-(2,4-difluorophenyl)-phenol from2,4-difluorophenylboronic acid and palladium oncharcoal/triphenylphosphine

A) 2,4-Difluorophenylboronic acid (1.10 g; 6.97 mmoles), prepared asdescribed in example 20, and ethanol (3 ml) were added to a mixture of5% palladium on charcoal (0.067 g; 0.0315 mmoles), toluene (12 ml),triphenylphosphine (0.033 g; 0.126 mmoles), 4-bromophenol (1.09 g; 6.3mmoles) and a 2M aqueous sodium carbonate solution (6 ml), kept understirring at 20° C. and under nitrogen.

The reaction mixture was heated under reflux and stirring for 16 hours.

While keeping under reflux, 37% hydrochloric acid (1.7 ml) was addeddropwise to the mixture.

The mixture was, then, filtered at warm by washing with warm acetone(2×10 ml).

The phases were separated and the aqueous phase was extracted withtoluene (5 ml).

The toluene phase and the acetone phase were collected and the resultantorganic solution was evaporated to dryness under reduced pressure.

The resultant crude (1.25 g; HPLC titre 75%) was purified by columnchromatography (silica gel, toluene) obtaining the desired compound (0.9g; 70% yield).

B) 2,4-Difluorophenylboronic acid (1.99 g; 12.6 mmoles), prepared asdescribed in example 20, and ethanol (3 ml) were added to a mixture of5% palladium on charcoal (0.0134 g; 0.0063 mmoles), toluene (12 ml),triphenylphosphine (0.0066 g; 0.0252 mmoles), 4-bromophenol (1.09 g; 6.3mmoles) and a 2M aqueous sodium carbonate solution (6 ml), kept understirring at 20° C. and under nitrogen.

The reaction mixture was heated under reflux and stirring for 20 hours.

While keeping at 60° C., 37% hydrochloric acid (1.7 ml) was addeddropwise to the reaction mixture.

The mixture was filtered at 50° C. by washing with acetone (2×10 ml) at50° C.

After separation of the phases, the aqueous phase was washed withtoluene (5 ml).

The collected organic phases were evaporated to dryness under reducedpressure obtaining 4-(2,4-difluorophenyl)-phenol (1.34 g; titre 87%; 90%yield).

C) 2,4-Difluorophenylboronic acid (1.1 g; 6.97 mmoles), prepared asdescribed in example 20, and ethanol (3 ml) were added to a mixture of5% palladium on charcoal (0.0134 g; 0.0063 mmoles), toluene (12 ml),triphenylphosphine (0.0066 g; 0.0252 mmoles), 4-bromophenol (1.09 g; 6.3mmoles) and a 2M aqueous sodium carbonate solution (6 ml), kept understirring at 20° C. and under nitrogen.

The reaction mixture was heated under reflux and stirring for 20 hours.

While keeping at 60° C., 37% hydrochloric acid (1.7 ml) was addeddropwise to the reaction mixture.

The mixture was filtered at 50° C. by washing with acetone (2×10 ml) at50° C.

After separation of the phases, the aqueous phase was washed withtoluene (5 ml).

The collected organic phases were evaporated to dryness under reducedpressure obtaining 4-(2,4-difluorophenyl)-phenol (1.25 g; titre 81%; 78%yield).

EXAMPLE 23 Preparation of 5-(2,4-difluorophenyl)-salicyclic acid from2,4-difluorophenylboronic acid and palladiumtetrakis(triphenylphosphine)

A) A mixture of 2,4-difluorophenylboronic acid (1 g; 6.3 mmoles),prepared as described in example 20, 5-bromosalicyclic acid (1.37 g; 6.3mmoles), toluene (4 ml), ethanol (1 ml), 2M aqueous sodium carbonatesolution (6 ml), palladium tetrakis(triphenylphosphine) (0.0366 g;0.0316 mmoles), prepared form PdCl₂ (Fluka) and triphenylphosphine(Fluka), and benzyltrimethylammoniumbromide (0.0725 g; 0.3 mmoles) washeated under reflux and stirring for 10 hours.

Then, the reaction mixture was poured into 2N hydrochloric acid (50 ml)and toluene (40 ml) and acetone (10 ml) were added.

The mixture was heated at 65° C. and the phases were separated at warm.

After drying, the organic phase wasevaporated to dryness under reducedpressure. The resultant crude (1.66 g; HPLC titre 58%) was purified bycolumn chromatography (silica gel, toluene:acetone:acetic acid=8:3:0.15)obtaining the desired compound (0.95 g; 60% yield).

B) A mixture of 5-bromosalicyclic acid (3 g; 13.8 mmoles), ethanol (2.3ml), a 2M aqueous sodium carbonate solution (21 ml) and palladiumtetrakis(triphenylphosphine) (0.073 g; 0.063 mmoles), prepared fromPdCl₂ (Fluka) and triphenylphosphine (Fluka), was heated at 80° C. In 10minutes, a solution of 2,4-difluorophenyl-boronic acid (2.75 g; titre94%; 16.4 mmoles), prepared as described in example 20, in ethanol (3.2ml) was added.

At the end of the addition, the reaction mixture was kept under stirringat 80° C. for 3 hours.

The resultant suspension was filtered obtaining5(2,4-difluorophenyl)-salicyclic acid (2.8 g; titre 86%; 70% yield).

C) By working as described in example 23(B) but substituting ethanolwith water, similar results were obtained.

What we claim is:
 1. A process for the preparation of a biphenylderivative of formula ##STR6## comprising the reaction between adifluorophenyl organometallic derivative of formula ##STR7## and aphenol compound of formula ##STR8## or the reaction between a phenolorganometallic derivative of formula ##STR9## and a difluorophenylcompound of formula ##STR10## wherein Q is a copper atom or an MX_(n)group where M is a metal selected from the group consisting of Mg, Zn,Cd, Hg, B and Alwith the proviso when M is Mg, Zn, Cd or Hg, X is Cl, Bror I and n is 1; when M is B, X is Cl, Br, I, OH, a C₁₋₃ alkoxy and n is2; when M is Al, X is C₁₋₄ alkyl and n is 2; Y is selected from thegroup consisting of Cl, Br, I and a trifluoromethanesulfonyloxy group;wherein R is selected from the group consisting of a hydrogen atom, alinear or branched C₁₋₅ alkyl, phenyl, substituted phenyl and benzyl; R₁is selected from the group consisting of a hydrogen atom, a carboxylgroup and a carboxyl precursor group; in the presence of a zero valenttransition-metal based catalyst.
 2. The process of claim 1, wherein saidzero valent transition-metal based catalyst is selected from the groupconsisting of Pd and Ni, optionally supported, in the presence ofligands.
 3. The process of claim 1, wherein said zero valenttransition-metal based catalyst is prepared in situ, started from a saltselected from the group consisting of NiCl₂, CoCl₂, Nickelacetylacetonate, FeCl₃, PdCl₂, Li₂ CuCl₄, palladium acetate andpalladium acetylacetonate.
 4. The process of claim 1, wherein said zerovalent transition metal base catalyst is selected from the groupconsisting of palladium tetrakis(triphenylphosphine), nickeltetrakis(triphenylphosphine) and palladium on charcoal in the presenceof triphenylphosphine.
 5. The process of claim 1, wherein Q is MX_(n),wherein M is Mg, X is Cl, Br or I, n is 1;Y is Cl, Br, I or atrifluoromethanesulfonyloxy group; and said zero valent transition-metalbased catalyst is palladium tetrakis(triphenylphosphine) or nickeltetrakis(triphenylphosphine).
 6. The process of claim 1, wherein Q isMX_(n), wherein M is B, X is OH, n is 2;Y is Cl, Br, I or atrifluoromethanesulfonyloxy group; and said zero valent transition-metalbased catalyst is palladium tetrakis(triphenylphosphine), nickeltetrakis(triphenylphosphine) or palladium on charcoal in the presence oftriphenylphosphine.
 7. A process for the preparation of5-(2,4-difluorophenyl)-salicylic acid comprising:i) reacting adifluorophenyl organometallic derivative of formula ##STR11## and aphenyl compound of formula ##STR12## or reacting a phenyl organometallicderivative of formula ##STR13## and a difluorophenyl compound of formula##STR14## wherein Q is a copper atom or an MX_(n) group where M is ametal selected from the group consisting of Mg, Zn, Cd, Hg, B and Alwiththe proviso when M is Mg, Zn, Cd or Hg, X is Cl, Br or I and n is 1;when M is B, X is Cl, Br, I or OH, a C₁₋₃ alkoxy and n is 2; when M isAl, X is C₁₋₄ alkyl and n is 2; Y is selected from the group consistingof Cl, Br, I or a trifluoromethanesulfonyloxy group; wherein R isselected from the group consisting of a hydrogen atom, a linear orbranched C₁₋₅ alkyl, phenyl, substituted phenyl or benzyl; R₁ isselected from the group consisting of a hydrogen atom, a carboxyl groupand a carboxyl precursor group; in the presence of a zero valenttransition-metal based catalyst; ii) hydrolyzing the --OR ether groupwhen R₁ ≠H; and iii) carboxylating the R₁ group when R₁ =H.
 8. Theprocess of claim 7, wherein said zero valent transition-metal basedcatalyst is selected from the group consisting of Pd and Ni, optionallysupported, in the presence of ligands.
 9. The process of claim 7,wherein said zero valent transition-metal based catalyst is prepared insitu, started from a salt selected from the group consisting of NiCl₂,CoCl₂, Nickel acetylacetonate, FeCl₃, PdCl₂, Li₂ CuCl₄, palladiumacetate and palladium acetylacetonate.
 10. The process of claim 7,wherein said zero valent transition metal base catalyst is selected fromthe group consisting of palladium tetrakis(triphenylphosphine), nickeltetrakis(triphenylphosphine) and palladium on charcoal in the presenceof triphenylphosphine.
 11. The process of claim 7, wherein Q is MX_(n),wherein M is Mg, X is Cl, Br, or I, n is 1;Y is Cl, Br, I or atrifluoromethanesulfonyloxy group; and said zero valent transition-metalbased catalyst is palladium tetrakis(triphenylphosphine) or nickeltetrakis(triphenylphosphine).
 12. The process of claim 7, wherein Q isMX_(n), wherein M is B, X is OH, n is 2;Y is Cl, Br, I or atrifluoromethanesulfonyloxy group; and said zero valent transition-metalbased catalyst is palladium tetrakis(triphenylphosphine), nickeltetrakis(triphenylphosphine), or palladium on charcoal in the presenceof triphenylphosphine.